The Clinical Research Program of the CNE studies the regulation of stress-responsive neuroendocrine systems and their relevance to the pathophysiology of illnesses such as major depression and inflammatory disorders. our studies employing continuous lumbar drainage of human CSF for 30 hours show that the secretion of the arousal producing neurohormone CRH shows a distinct circadian pattern in human CSF; the mean amplitude of basal circadian CSF CRH is elevated during melancholic depression and falls significantly following electroconvulsive shock-induced remission. Basal norepinephrine spillover into arterial plasma and its responses to alpha-2 adrenoreceptor blockade are also significantly higher in melancholia and both in significantly following remission. We showed that graded levels of exercise based on percent maximal oxygen utilization produce dose-dependent increases in plasma ACTH, cortisol, vasopressin, and sympathomedullary responses that are independent of physical conditioning and absolute work-load; This paradigm represents the application of a quantifiable, naturalistic stressor that produces dose-dependent responses that are independent of the variable most likely to produce confounding individual variation. Patients with seasonal affective disorder show responses to this paradigm indicating hypoactivity of stress-responsive systems depressed phase that are corrected by successful treatment. These abnormalities persist with spontaneous recovery as well and thus constitute potential state independent markers. Our data show that the pathophysiology of hypercortisolism in melancholia is distinct from that seen during chronic inflammation, suggesting that hypercortisolism in depression is not simply an epiphenomenon of the stress of a chronic illness. Chronic tricylic antidepressant to the rat decreases CRH mRNA levels in the hypothalamus and in vivo pituitary-adrenal function and produces a subtle, centrally-mediated hypocortisolism in healthy controls. The latter data suggest that down-regulation of arousal- producing neurotransmitter systems may represent an important mechanism of action of antidepressant agents.